Smaller forms of amyloid a possible target for Alzheimer's

In a new study published in the scientific journal Neurology, scientists at Karolinska Institutet show that smaller forms of amyloid known as oligomers may be significant in the development of Alzheimer's disease – and are therefore a possible target for future drugs. These new findings add another piece to the puzzle of the complex dementia disease that affects so many people.

The formation and accumulation of amyloid in the form of plaques in the brain has long been considered one of the main causes of Alzheimer's disease. But alternative or complementary explanations also exist. In this present study Professor Agneta Nordberg and her team at the Division of Alzheimer Neurobiology Centre show that amyloid plaque in the brain is not always critical to the formation of symptoms and the progression of the disease, but that there can be even smaller, even more harmful amyloids that, unlike the plaque, are tiny enough to penetrate into the actual neurons.

The researchers used a PET scanner to study eight members of a family with a congenital form of Alzheimer's disease linked to a mutation in chromosome 21, known as the Arctic mutation. Doing so, they discovered that both family members with clinically confirmed Alzheimer's and symptom-free carriers of the Arctic mutation had no amyloid plaque in the brain. The scans they produced were comparable with those of the brains of healthy people who lack this mutation, but differed to those of patients with non-inherited Alzheimer's or carriers of other known mutations associated with the disease.

However, despite the absence of amyloid plaque, carriers of the Arctic mutation displayed memory impairments and pathological changes in their cerebrospinal fluid related, for example, to the presence of amyloids. The researchers also observed reduced glucose metabolism in the brain, an indication that neuronal function has been affected by harmful oligomers.

"We can therefore draw the conclusion that the presence of amyloid plaque in the brain is not solely responsible for the impairment of brain function and memory, and that the amyloid plaque measured in the brain does not fully square with that measured in the CSF," says Professor Nordberg. "Our study supports the assumption that medical therapies should also be targeted at the oligomers."

It is estimated that over 35 million people worldwide suffer from some form of dementia, Alzheimer's disease being the most common. The form known as sporadic Alzheimer's, for which scientists have been unable to pinpoint any genetic causes, make up the majority of cases. Amyloid is a form of protein accumulation that also includes other biochemical substances.